P1278: MEASURABLE RESIDUAL DISEASE ASSESSMENT IN THE PROSPECTIVE HAPLOMUD STUDY
Authors: Isabell Arnhardt, Arnold Kloos, Nadine Kattre, Razif Gabdoulline, Alina Lasch, Yasmine Alwie, Nicolaus Kröger, Rudolf Trenschel, Matthias Stelljes, Matthias Eder, Wolfgang Bethge, Gesine Bug, Carlos Solano Vercet, Jaime Sanz, Fermin Sanchez-Guijo, Alessandro Rambaldi, Francesca Bonifazi, Francesca Patriarca, Marketa Šťastná Marková, Philipp Wohlfarth, Hildegard Greinix, Adrian Schwarzer, Michael Heuser
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: Allogeneic hematopoietic stem cell transplantation (alloHCT) is a common treatment option for younger or relapsed patients with acute leukemia. The disease burden during and after therapy can be monitored by determining measurable residual disease (MRD). MRD has been established as a prognostic biomarker for relapse incidence and survival. The HaploMUD trial is an ongoing, European, prospective clinical trial. It was initiated to determine outcome differences between matched unrelated (MUD) and haploidentical donor alloHCT in patients with acute leukemia using the same graft-versus-host disease (GvHD) prophylaxis. The translational program focuses on MRD assessment. We hypothesize that haploidentical alloHCT will reduce the relapse rate in MRD+ AML patients. Aims: The translational program aims to establish MRD as a prognostic biomarker to guide the use of alloHCT. To clarify, whether haploidentical alloHCT is superior to MUD alloHCT in MRD+ patients, the MRD status of subjects included in the HaploMUD trial was evaluated at two time points. Methods: Bone marrow aspirate (BM) and peripheral blood (PB) were acquired prior to alloHCT (baseline sample (BS)) and 6 months afterwards (follow-up sample (FU)). Error-corrected next-generation sequencing (NGS) and multiparameter flow cytometry (MFC) were performed in one central laboratory to assess MRD status. Molecular mutations in the diagnostic sample are analyzed in BM and PB with NGS in the BS and FU samples. MFC-MRD is based on aberrantly expressed surface marker combinations on leukemic blasts in BM. Those leukemia-associated immunophenotypes (LAIPs) were identified in the local laboratories at diagnosis and traced during follow-up or aberrant cell populations were identified regardless of the diagnosis (different from normal approach). To identify the LAIPs a five tube 8-color panel was used. Results: 77 subjects have been enrolled in the translational program so far. The majority (71%) were diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and 29% with acute lymphoblastic leukemia (ALL). All 55 AML and MDS BS and 29 FU samples were analyzed by with one method, 23 BS and 6 FU samples with both. Using MFC, 35% of the BS were MRD+ at a threshold of 0.1%, whereas 21% of the FU samples were still MRD+. Similarly, 42% of the BS were found MRD+ with NGS analysis using the optimal cutoff (average 0.02%). After 6 months only 14% of the samples were found to be NGS-MRD+. Twelve different LAIPs were identified, with CD34+CD13+HLADR- and CD34+CD13+CD7+ being the most frequently observed. 29 mutated genes were analyzed by NGS. The most frequently evaluated genes were DNMT3A and ASXL1. The samples had a median of 3 (range: 1-5) mutated genes. For 19 BS, BM and PB were analyzed with NGS. 84% had the same MRD outcome in both tissues. Of the samples measured with both MRD methods, 74% BS and 75% FU samples had the same MRD result independent of the MRD technology. Summary/Conclusion Prospective MRD assessment before and after alloHCT with MFC and NGS MRD identifies a similar proportion of patients as MRD+ before alloHCT (35-42%) and after alloHCT (14-21%). The study is ongoing and prognostic and predictive effects of MRD will be evaluated after trial completion. Keywords: Allogeneic hematopoietic stem cell transplant, Acute leukemia, MDR, Clinical trial